Support is requested for the development and implementation of novel computational methods for simulating the long timestep dynamics of proteins and the application of these methods to study the relation between motions and biological functions in flexible proteins. This will satisfy an urgent need for high-fidelity methos that reach biologically relevant timescales of microseconds to milliseconds of simulation, rather than the nanoseconds to microseconds simulations that are commonly available. While conformational change has itself been studied computationally for many years, our proposed work differs from other approaches in (1) the high-performance implementation of novel methods for long timestep dynamics and enhanced sampling at all-atom resolution and (2) the application of these detailed methods to address questions of flexibility and function in biomolecules of biomedical relevance. Since a quantitative comparison to experiment is critical for both the testing and greater impact of our computational methods, experimental collaborations are proposed. These are documented by letters of support. This project will have a widespread impact on NIH-funded researchers because the target parallel software packages already have a large user base and have an open code source. Longer MD simulations will allow previously impossible studies to be carried out in the fields of protein folding, protein engineering, enzyme design, drug design to flexible targets, and interactions among protein and nucleic acid complexes.